Yamazaki Naoya, Kiyohara Yoshio, Uhara Hisashi, Uehara Jiro, Fujimoto Manabu, Takenouchi Tatsuya, Otsuka Masaki, Uchi Hiroshi, Ihn Hironobu, Minami Hironobu
Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Dermatology Division, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
Cancer Sci. 2017 Jun;108(6):1223-1230. doi: 10.1111/cas.13241. Epub 2017 Jun 15.
Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation through overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI-142533.).
治疗晚期或复发性黑色素瘤仍然是一项挑战。癌细胞可通过过度表达抑制性受体程序性死亡1（PD-1）配体来阻断T细胞活化，从而逃避免疫系统。PD-1抑制剂纳武单抗可阻断T细胞中的抑制信号，从而克服癌细胞的免疫抗性。纳武单抗在各种癌症中均显示出有前景的抗癌活性。我们开展了一项单臂、开放标签、多中心的II期研究，以调查纳武单抗在既往未接受治疗的日本晚期黑色素瘤患者中的疗效和安全性。24例III/IV期或复发性黑色素瘤患者入组，每2周静脉注射纳武单抗3 mg/kg，直至疾病进展或出现不可接受的毒性。主要终点为由独立放射学审查委员会评估的总缓解率。独立放射学审查委员会评估的总缓解率为34.8%（90%置信区间为20.8 - 51.9），18个月时的总生存率为56.5%（90%置信区间为38.0 - 71.4）。3级或4级治疗相关不良事件仅发生在3例患者中（12.5%）。2例患者因不良事件停用纳武单抗，但所有不良事件通过早期诊断和适当治疗均被认为可控制。亚组分析表明，无论BRAF基因型如何，纳武单抗在临床上均有益且耐受性良好，且发生治疗相关特定不良事件和白癜风的患者显示出更好的生存趋势。总之，纳武单抗在有或无BRAF突变的日本晚期或复发性黑色素瘤患者中均显示出良好的疗效和安全性。（试验注册号：JapicCTI-142533。）
